Process for the production of 16alpha-methyl-17alpha-hydroxy-pregnane-20-ones and intermediates therefor



United States Patent Ofifice 3,122,573 Patented Feb. 25, 1954 The present invention has as its object a process for the preparatoin of keto-steroids, and more particularly for the preparation of 1Sat-methyl-17a-hydr0xy-pregnane- 20 ones of the general formula:

w l U V wherein R is H or and R is H or an acyl radical, and the group RO may be attached in the aor ,S-position.

These compounds are intermediate products in the synthesis of 115,17a,2l-trihydroxy-16a-methy1-9rx-fiuoro-A pregnadiene-3,20-dione, a compound which has been described by Arth et al., I. Am. Chem. Soc. "80, 3161 (1958), as exhibiting an activity such that it may be used clinically in doses which are from one seventh to one tenth the amount of the most active corticosteroids heretofore employed.

Previously, in order to synthesize the hydroxylated pregnadiones V (R O), the starting material according to the literature (Arth at 211., J. Am. Chem. Soc, 1958, vol. 80, page 3160) is a 3a-acyloxy-A -pregnane-l1,20- dione or, according to Oliveto et 21., I. Am. Chem. Soc., 1958, vol. 80, page 4431, from a Bfi-hydrQXy-A -pregnane- 20-one. In both cases the methyl radical is introduced into the 160: position by means of a Grignard reagent, but the yields are low because of the difficulty of achieving the 1,4- addition without attacking the carbonyl functions in the 20 and 11 positions. Thus, in its Belgian Patent 568,015 of May 24, 1958, Merck discloses a yield of about 25% The Met-methylated compound is hydroxyiated in the 170: position by the process of Gallagher, J. Am. Chem. Soc. 72, page 882 (1950), by enoiization of the keto function in the 20 position, formation of the epoxide across the double bond in the 17,20 positions thus created and saponification of this epoxide. This last operation at the same time liberates the hydroxyl radical in the 3 position which, if it is not previously protected, is acetylated in the course of the enolization. The methylation of the carbon atom in the 16 position makes it difficult to obtain the l7-hydr0xylated derivatives in the pure state by this method; thus, it is diflicult to surpass a yield of to in this second stage.

In accordance with the process of the present invention, the above stated object is accomplished by operating in accordance with the schematic flow sheet in Table I and the following stepwise analysis.

TABLE I I3 RIOWCKD CH.

3 STAGE 1 Preparation Compound 11 Compound I, a 30:- or 3p-acyloxy-16-methyl-A -pregnene-ZG-one wherein R is :0 or H and R is H or the acyl radical of a hydrocarbon carboxylic acid having less than twelve carbon atoms and selected from the group consisting of lower alkanoic acids, e.g., acetic acid, propionic acid or butanoic acid; aromatic acids, e.g., benzoic acid or p-toluic acid; aralkanoic acids, e.g., phenylacetic acid; and aralkenoic acids, e.g., cinnamic acid, is treated with an agent capable of forming an epoxy linkage across the double bond in the 16,17 position. Suitably employed for this purpose are peroxide compounds, such as hydrogen peroxide in an alkaline medium, using conventional epoxidation conditions. This epoxidation effected in an alkaline medium simultaneously produces a deacylation of the hydroxyl radical at the 3 position. Compound II thus prepared may be used as such for succeeding operations, or if desired, may be purified by conventional purification procedures.

Compound I is prepared by the conventional method of pyrolyzing the pyrazoline formed by the action of diazomethane on a 3-acyloxy-A -pregnene-20-one.

STAGE 11 Preparation of Compound 11] Compound II is treated with a functional derivative of a carboxylic acid of the aforementioned group of acids useful for forming the 3-acyloxy derivatives. Suitable functional derivatives are acid halides, such as acetyl chloride and propionyl chloride; and carboxylic acid anhydrides such as acetic acid anhydride. The acrylation reaction is conducted in the presence of a basic material such as an organic base, a preferred base being pyridine. Compound Ill may be employed as such, or first neutralized either by water washing per se, or contacted with a weakly alkaline solution such as aqueous sodium bicarbonate.

STAGE III A. Preparation of Compound 1 Va by Reacting Compound 111 With a Hydrohalic Acid (1) Compound III is treated with hydrogen chloride in an anhydrous solvent. The concentration of the hydrogen chloride is approximately 5 to percent, and preferably 6%. The solvent medium may be any organic liquid in which the steroid is soluble and which is inert to reaction conditions. A suitable solvent is glacial acetic acid. The reaction mixture should be externally cooled and is allowed to stand at lowered temperature until reaction is effected. Separation of the Compound IVa may be facilitated by the action to the reaction medium of a solvent such as ether in which the product is insoluble. The product may be used as such, or purified by conventional means prior to use in subsequent reactions.

Alternativel' Compound IVn may be prepared as follows:

(2) Compound III is dissolved in an inert solvent, such as acetic acid, and then quickly treated with concentrated aqueous hydroiodic acid dissolved in the same solvent. The temperature is controlled by external cooling with cold water. After a short time, Compound IVa crystallizes out of solution and may be used as such or further purified for use in subsequent operations.

B. Preparation of Compound IVb Compound III is treated with a dilute solution of hydroiodic acid in acetic acid. The hydroiodic acid which should have a concentration of less than 20% and preferably about 18% is prepared by mixing aqueous hydroiodic acid with acetic acid until the proper concentration is attained. The addition of the hydroiodic acid to the steroid is accomplished gradually and should be effected over a period of from fifteen to 30 minutes. The reaction mixture is allowed to stand and is then hydrin (l7u-OH-16p-Br) or to an unsaturated compound, 7

as one would expect, but rather to 3u-acyloxy-l6-halo methyl-A -pregnene-2O-one (VI). In contrast thereto,

the dilute hydracids lead to the characteristic results of the present invention.

STAGE IV A. Preparation of Compound V From Compound lVa Compound IVa is catalytically hydrogenated by contact with hydrogen in the presence of an alcoholic suspension of the hydrogenation catalyst to reduce the exocyclic double bond. Suitable reaction media involve the use of the lower alkanols, such as ethanol, or isopropanols and conventional hydrogenation catalysts. -A preferred catalyst is palladium on charcoal. The reaction is conducted under superatmospheric pressure in conventional hydrogenation equipment. The reaction is continued until a theoretical amount of hydrogen has been absorbed. Compound V is separated from the hydrogenation mixture by filtration and may be, if desired, purified by conventional purification methods.

B. Preparation of Compound V From Compound IVb Compound V is prepared by hydrogenation of Compound IVb according to the procedure outlined for the hydrogenation of Compound IVa by reduction of the endocyclic double bond.

By the reduction of the exocyclic double bond of Compound IVn or reduction of the endocyclic double bond of Compound lVb, Compound V in the form of an acyl derivative, e.g., 3-acyloxy-l7a-hydroxy-16amethyl-pregnane-20-ones is obtained (with or without a ketone function in the 11 position, depending upon the starting material used). This result was unexpected since, for example, hydrogenation of Compound I yields the corresponding 16,8-methyl derivative, whereas Compound V obtained according to the process of the invention is a 16a-configurated derivative; the small quantities of the Si-isomer which simultaneously formed remaining dissolved in the crystallization liquor. of Compound V in the form of its 3-acylated derivatives the corresponding hydroxy derivatives are obtained (R'=H).

In the event that unconverted Compound III is recovered from the reaction product containing either Compound IVa or Compound IVb, it can advantageously by reconverted to the starting steroid, Compound I, by treatment with hydrohalic acid preferably in a solvent such as acetic acid and in the presence of dioxane to yield Compound VI which in turn can be converted by reduction with Zinc and acetic acid to starting Compound I and then reused for synthetic method invention.

Thus, as has been described above, the process according to the present invention makes it possible for the first time to obtain mot-methylated derivatives by starting.

rials, Compound I, for example, either a 3cc-acyloxy l6-methyl-A -pregnene-11,20-dione or a 3fi-acyloxy-l6 methyl-A -pregnene-Zlhone, may be used as the starting material, both of which are readily accessible, the first;

By saponification of this acetic acid anhydride.

by starting from a 3a-acyloxy-A -pregnene-11,2O-dione and the second by starting from commercial pregnadieneolone in accordance with the method described in the literature (Wettstein, Helv. Chim. Acta, 1944, vol. 27, page 1803). The derivatives, Compounds V (R=H which do not carry a keto function in the 11 position may be converted into Compounds V (R=O) by subjecting them to microbiological hydroxylation in the 11 position in accordance with known methods (i.e., fermentation by a micro-organism of the genus Rhizopus sp.) followed by chrornic oxidation.

The following examples illustrate the invention without, however, limiting it, particularly with respect to the choice of the starting material, the fundamental characteristic of which is the double bond in the 16,17 position.

EXAMPLE 1 Preparation of 301,]7m-Dihydr0xy-16a-Methyl-Pregnane- JLZO-Dione V Starting With 3a-Acet0xy-16-Methyl- A Pregnene-11,20-Di0ne (I) (R=O, R'=CH CO) STAGE 1.-PREPARATION 0F 3cx-HYDROXY-16B-METH- llilg,l7a-EPOXY-PREGNANE-lLZO-DIONE (II) 11:0,

1.5 gm. of the dione I are dissolved at room temperature in 80 cc. of methanol and 3 cc. of 4 N sodium hydroxide are added to this solution while maintaining the temperature at 15 C. by external cooling with an ice bath. Thereafter, 6 cc. of a 110 volume hydrogen peroxide solution are added; the temperature is maintained between 15 and C. for minutes and the solution is allowed to stand overnight in the refrigerator. Another 6 cc. of a 110 volume hydrogen peroxide solution are added, the temperature is again maintained between 15 and 20 C. for 30 minutes, and the solution is allowed to stand overnight in the refrigerator. The next day the reaction mixture is poured into ice Water and the 3e-hydroxy-16B-methyl-l6oa,17a-epoxy-pregnane 11,20-dione (i1), precipitated thereby, is separated by vacuum filtration. The filter cake is washed with water until the wash Water is neutral and dried yielding 1.2 gms.

(yield, 85% of theoretical) of the dione (l1), melting point, 176177 C., of sufficient purity for use in subsequent reactions. For analysis, the product is recrystailized from ethyl acetate, whereupon it has a melting point of 177.5 C. and a specific rotation of [a] =+97il (c.=l% in chloroform).

AnalysiS.C I-I O molecular weight=350.5. Calculated: C, 73.93%; H, 8.9%. Found: C, 73.9%;

It is soluble in acetic acid (3 volumes), ethyl acetate (6 volumes), acetone and chlorinated solvents; slightly soluble in isopropyl ether, ethyl alcohol and methyl alcohol; and insoluble in Water, ethyl ether and cyclohexane. This compound is not described in the literature.

STAGE 2.PRE'PARATION OF 3a-ACETOXY16B-METH- YL 16a,17a EPOXY PREGNANE-1L20-DIONE, (III).

(11:0, RzCHaCO) STARTING FROM COBIPOUND II A mixture of 1.5 gm. of Compound 11, prepared according to the preceding stage, 1.5 cc. of pyridine and 3 cc. of acetic acid anhydride is refluxed for one and a half hours. The mixture is allowed to cool to room temperature and is then poured into ice water, wherein it is allowed to stand for 30 minutes to destroy the excess Crude Compound III is separated by vacuum filtration, washed by trituration with distilled water and dried. 1.67 gms. of 3u-acetoxy-16B-methyl- 16a,17a-epoxy-pregnane-11,20-dione, M.P. 164 C. (which is a yield of 99.7%) are obtained which may be used as such for the subsequent operations.

For analysis, the crude product is recrystallized from ethanol and the crystals having a melting point of 166- 166.5 C. and a specific rotation of [cc] =+l09 (c.=1 %in chloroform). The ultraviolet spectrum shows the absence of the A -ene-20-one group.

The product is very soluble in chlorinated solvents;

is slow and lasts approximately 15 minutes.

soluble in benzene, toluene and ethyl acetate, slightly soluble in ethanol, methanol and isopropyl ether; very slightly soluble in petroleum ether and cyclohexane; and insoluble in water.

Analysis.C I-I O molecular weight=402.5l. Calculated: C, 71.6%; H, 8.5%. Found: C, 71.8%; H, 8.6%.

STAGE safennmnnrron on 3a-AGETOXY-17uHY- DROXY-l6-\IETHYLENE-PREGNANE-11,20-DIONE 1V0.)

(R=O, R=CHsCO) STARTING WITH EPOXIDE III (1) A stream of anhydrous gaseous hydrochloric acid is passed into 50 cc. of acetic acid which is externally cooled with cold water, until the solution titrates approximately 6% hydrochloric acid by weight. 12 cc. of this solution are introduced, accompanied by mechanical agitation, over a period of 2 to 5 minutes by means of a dropping funnel into a suspension of 4 gm. of the acetylated epoxide III in 8 cc. anhydrous ether, cooled to 0 C. The solution dissolves in approximately 10 minutes, and Compound IVa begins to crystallize out 10 minutes after solution is completed. Agitation is continued for 30 more minutes after which the precipitated derivative Va is separated by vacuum filtration, washed with ether until the wash ether shows no more acidity and dried. 2.6 gm. to 2.8 gm. (a yield of about 6570%) of the 3a-acetoxy- 17a hydroxy-16-methylene-pregnane-l1,20-dione (IVa) are obtained having a melting point of 218 C. This product can be used as such for the subsequent operations. By evaporation of the mother liquor and precipitation from water, an additional 0.8 gm. are obtained.

For analysis, the first batch of product is recrystallized 'from methanol, yielding colorless prisms having a melting point of 225 C. and a specific rotation of Da e-14 c.=1.% in chloroform), which are soluble in cold chlorinated solvents, soluble in hot methanol and slightly soluble in cold methanol, ethanol, ethyl acetate and isopropyl ether.

Analysis.C H O molecular weight=40=2.5l. Calculated: C, 71.6%; H, 8.5%; O, 19.9%. Found: C, 71.8%; H, 8.5%; O, 20.3%.

Alternatively, Compound IVa is prepared as follows:

(2) 1 gm. of the acetylated epoxide III is dissolved in 7 cc. of acetic acid and treated quickly with 5 cc. of a hydroiodic acid solution (prepared by mixing 5 cc. of a 57% hydroiodic acid solution in water with 20 cc. of acetic acid) at a temperature between 15 and 20 C. After 10 minutes of standing 15 cc. of Water are added, the mixture is vacuum filtered and the crystalline filter cake is washed and dried. 0.66 gm. of 3a-acetoxy17ahydroXy-l6-methylene-pregnane-11,20-dione (IVa) (melting point, 199 C. and a 66% yield) are obtained. After purification in methanol, the product melts at 221 C.

STAgE 3b.-PREPARATION OF 30z-ACETOXY 17 u-HY- D OXY 16 METHYL A PREGNENE 11,20-DI- IgljVb) R=O, R =CI-I3CO, STARTING WITH EPOX- 20 cc. of an 18% solution of hydroiodic acid in acetic acid (obtained by mixing 5 cc. of a 57% hydroiodic acid with a suificient quantity of acetic acid to make a total of 25 cc.) are introduced by means of a dropping funnel into a solution under agitation of 4 gm. of Compound III obtained according to Stage 2 dissolved in 28 cc. of acetic acid. The introduction of the hydroiodic acid solution The agitation is continued for '15 minutes at ambient temperature and then 40 cc. of water are added slowly and crystallization is initiated by scratching. After one-halt hour of agitation, the crystals are separated on a vacuum filter, washed with Water until neutral and dried. 2.6 to 2.8 gm. of 30a acetoxy-lh-hydroxy-l6-methyl-A -pregnene-11,20-dione (lVb), melting point=191 C. (a yield of 65 to 70%) are thus obtained. For analysis, the product is recrystallized from methanol and has a melting point of 195 C. and a specific rotation of [a] =-16 (c.=l% in chloroform). Compound IVb is obtained in the form of rather large needles, it is soluble in chlorinated solvents and acetone, fairly soluble in ethylene acetate, soluble in hot and slightly soluble in cold methanol and ethanol and isopropyl ether.

AnaZysis.-C H molecular weight- 402.51. Ca1- culated: C, 71.6%; H, 8.5%; O, 19.9%. Found: C, 71.8%; H, 8.6%; O, 19.8%.

STAGE 4a.PREPARAlTION OF 3zrACETOXY-l7aHY- DROXY 16a BETHYL PREGNANE11,20-DIONE (V) (3:0, R =1'CH3CO) STARTING WITH DERIVATIVE I o 1 gm. of compound lVa is suspended in 80 cc. ethanol in a hydrogenation apparatus and the resulting suspension is agitated. Solution is almost complete. Paliadized charcoal (prepared by customary methods from 500 mgm. of charcoal and 0.5 cc. of a solution of palladium chloride containing 20% palladium) is added. After purging the air from the vessel the mixture is hydrogenated. The absorption of the theoretical quantity of hydrogen takes place in minutes. Agitation is continued for minutes in atmosphere of hydrogen and then the charcoal is filtered off and washed with alcohol. The filtrate and the wash alcohol are combined and evaporated to dryness in vacuo. The residue, taken up in 2 cc. ethanol, is iced causing a crystalline precipitate which is separated on a vacuum filter and dried. 750 mgm. of 3a-acetoxy-l7ahydroxy-16u-methyl-pregnane-11,20-dione (V) having a melting point of 186 C. and a specific rotation of [a] :-}54.5 (c.=l% in chloroform), are thus obtained. After recrystallization from ethanol, the product is obtained in the form of square crystals. Recrystal lization from isopropyl ether yields the same product in the form of needles. The product is very soluble in chlorinated solvents, soluble in ethanol and isopropyl ether, slightly soluble in ethyl ether and insoluble in water.

Anazysis.-C H O molecular weight404.52. Calculated: C, 71.25%; H, 8.97%; O, 19.77%. Found: C, 71.4%; H, 8.9%; O, 19.8%.

STAGE 4b.PREPARATION OF Zia-ACETOXYJTa-HY- DROXY-lSoz-M'ETHYL PREGNANE 11,20 DIONE (V) :(rlbz O, R :CHsCO) STARTING FROM DERIVATIVE The reaction described in Stage 4a is repeated using 1 gm. of Compound IVb. The hydrogenation proceeds somewhat more slowly yielding a crystallized product,

' acetoxy 17cc hydroxy-16a-methyl-pregnane-11,20-dione (V), in 65% yield. The melting point, specific rotation, analysis and spectrum are exactly identical to Compound V obtained in Stage 4a, and admixture of the two does not produce a depression in the melting point.

EXAMPLE II Preparation of 3a,]7oc-Dthydroxy-16a-Methyl-Pregnane- 11,20-Di0ne (V) (R=O, R'=H), Starting With Its Acetate (V) (R'=CH CO) A mixture of 1 gm. of the acetate of Compound V (R'=CH CO) and 10 cc. of 1 N methanolic potassium hydroxide (prepared by dissolving 8 cc. of 48 B. aqueous potassium hydroxide in a suificient quantity of methanol to make 100 cc.) is heated under reflux until the acetate dissolves and the resulting solution is agitated for 1 hour at 40 to C. The reaction mixture is precipitated in water, the precipitate is separated by vacuum filtration, the filter cake is washed with water until the wash water is neutral, again vacuum filtered and dried. 3oz,17a-dihydroxy-lGa-methyI-preguane-I1,20-dione (V) (R=H) is obtained in a quantitative yield.

EXAMPLE HI Preparation of 3u-Acetoxy-I6-Br0m0methyl-A Pregnene-l 1,20-Dione (VI) A solution containing 55% by weight of hydrobrornic acid in acetic acid is prepared by bubbling anhydrous hy- 8 drobromic acid through cc. of acetic acid. 40 cc. of this solution are introduced over a period of 5 minutes with the aid of a dropping funnel into a suspension of 10 gm. of epoxide III, prepared according to Example 1, Stage 2, in 20 cc. of dioxane cooled to 0 C., while mechanically agitating. Agitation is continued for 3 hours at 0 C., and then the thick, yellowish-orange reaction mixture is poured into a mixture of ice and water. The brominated derivative VI precipitates out. until neutral, dried, and recrystallized by dissolving it in methylene chloride and adding isopropyl ether to the solution until crystallization begins. brornomethyl A pregnene-11,20-dione (Vi) having a melting point of 199 C. is soluble in chlorinated solvents, dirnethyl formarnide and acetone, fairly soluble in cold acetic acid, soluble in hot methanol and hot ethanol from which it recrystallizes by cooling. The

ultraviolet spectrum shows a maximum of 251 m e:10,550, and a specific rotation of [a] =125 (c.=l% in chloroform).

Analysis.C H O Br; molecular weight 465 .42. Calculated: C, 61.93%; H, 7.15%; O, 13.75%; Br, 17.17%. Found: C, 62.4%; H, 7.2%; O, 14.1%; Br, 16.8%.

Treated with zinc and acetic acid Compound VI yields Compound I. This compound is not described in the literature.

The description of the operative details given in the above examples is in no Way limiting and does not constitute any more than a preferred mode of operation. Thus, it is possible to vary the temperatures, the nature of the solvents or to employ equivalent techniques with another acylation agent or saponification agent without departing from the spirit of the invention. In addition, instead of utilizing the starting acetoxylated derivative 1, it is possible to start with any other 3-acyloxylated derivative and also to acylate Compound 11 with the anhydrides of other acids, such as of propionic acid or benzoic acid, etc. spirit of the inventionand the scope of the appended claims.

We claim:

1. A compound having the formula:

m RIOWCIQ 011.

wherein R is a member selected from the group consisting of hydrogen and an acyl radicalof a hydrocarbon carboxylic acid having less than twelve carbon atoms.

2. The compound of claim 1 wherein R'O is acetoxy in the a orientation. 7

3. A compound having the formula It is washed with water 3a-acetoxy 16- Any such changes and modifications are Within the 5. A compound of the formula:

I \/\CHQBI ROMN wherein R is a member selected from the group consisting of hydrogen and acyl radical of a hydrocarbon carboxylic acid having less than twelve carbon atoms.

6. The compound of claim 5 wherein R'O is a hydroxy group in the at orientation.

7. The process for the preparation of the compound of the formula:

CO-OHa i/WW i CH3 RONW wherein R is a member selected from the group consisting of oxygen and H and R is a member selected from the group consisting of hydrogen and acyl radical of a hydrocarbon carboxylic acid having less than twelve carbon atoms which comprises reacting a compound of the formula:

COCH3 .OMQU

wherein R and R are as defined above, with anhydrous hydrobromic acid to obtain the compound of the yon wherein R is a member selected from the group consisting of H and oxygen and R is a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having less than twelve carbon atoms, which comprises quickly contacting a compound of the formula:

wherein R and R have the above described meaning with concentrated aqueous hydroiodic acid.

9. The process for preparing a compound of the formula wherein R is a member selected from the group consisting of H and oxygen and R is a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having less than twelve carbon atoms which comprises slowly reacting a com pound of the formula:

wherein R and R have the above described meaning with a dilute aqueous solution of hydroiodic acid.

References (Iited in the file of this patent UNITED STATES PATENTS 2,677,695 Oliveto et a1. May 4, 1954 2,705,233 Julian Mar. 29, 1955 2,740,783 Hogg et a1. Apr. 3, 1956 2,752,339 Julian et al. June 26, 1956 2,865,808 Agnello et a1 Dec. 23, 1958 2,958,702 Taub et al. Nov. 1, 1960 2,985,563 Carvajal May 23, 1961 OTHER REFERENCES Arth et al.: 80 J.A.C.S. 3160 (1958). Slates et al.: 81 J.A.C.S. 5472- (1959). Fieser and Fieser: Steroids (1959), p. 360.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,122,573 February 25, 1964 Gerard Nomine et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below,

Columns 1 and 2, formula IVa should appear as-shown below instead of as in the patent:

CID-CH Signed and sealed this 3rd day of November 1964.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of-Patents ERNEST w, SWIDER Attesting Officer 

1. A COMPOUND HAVING THE FORMULA
 7. THE PROCESS FOR THE PREPARATION OF THE COMPOUND OF THE FORMULA: 